1,2- Vs 1,4-Regioselectivity of Lithiated Phenylacetonitrile toward α,βUnsaturated Carbonyl Compounds. 2. Relation between the Regioselectivity and the Structure of the Species in Solution

Article abstract of DOI:10.1021/jo9715175

In THF and THF-toluene media, the reaction of lithiated phenylacetonitrile (1) with benzylide-neacetone (5), at low temperature, led to the same ratio of 1,2- and 1,4-adducts after 5 or 30 min of reaction time. The concentrations of the monomeric bridged ion pair 2 preferentially formed in THF and of the dimer of ion pairs 4 predominating in media that favor association such as THF-toluene solvent mixtures were measured from the IR-integrated intensities of the v (C≡N) bands. These concentrations were quantitatively related to the concentrations of the 1,2- and 1,4-adducts, respectively. All these results evidence the kinetic control of this reaction. Intermediate complexes that take into account the peculiar geometries of the monomer 2 and the dimer 4 are proposed to interpret the different regioselectivities observed with 5. This study is extended to cyclic α-enones and cinnamaldehyde. Similar trends hold for the former, while cinnamaldehyde always leads to 1,2-addition. The formation of intermediate complexes allows us to rationalize the cinnamaldehyde behavior but is insufficient to explain the 1,4-addition with cyclic α-enones lying in an s-trans conformation.

Full text of DOI:10.1021/jo9715175

J . Org. Chem. 1998, 63, 3295-3301
3295
1,2- vs 1,4-Regioselectivity of Lith ia ted P h en yla ceton itr ile tow a r d
r,â-Un sa tu r a ted Ca r bon yl Com p ou n d s. 2. Rela tion betw een th e
Regioselectivity a n d th e Str u ctu r e of th e Sp ecies in Solu tion
Tekla Strzalko, J acqueline Seyden-Penne, and Lya Wartski*
Institut de Chimie Mole´culaire d’Orsay, URA CNRS 478, 91405 Orsay, France
J acques Corset,* Martine Castella-Ventura, and Franc¸oise Froment
LASIR, CNRS, UPR 2631, B.P. 28, 94320 Thiais, France
Received J uly 30, 1996 (Revised Manuscript Received August 6, 1997)
In THF and THF-toluene media, the reaction of lithiated phenylacetonitrile (1) with benzylide-
neacetone (5), at low temperature, led to the same ratio of 1,2- and 1,4-adducts after 5 or 30 min
of reaction time. The concentrations of the monomeric bridged ion pair 2 preferentially formed in
THF and of the dimer of ion pairs 4 predominating in media that favor association such as THF-
toluene solvent mixtures were measured from the IR-integrated intensities of the ν (CtN) bands.
These concentrations were quantitatively related to the concentrations of the 1,2- and 1,4-adducts,
respectively. All these results evidence the kinetic control of this reaction. Intermediate complexes
that take into account the peculiar geometries of the monomer 2 and the dimer 4 are proposed to
interpret the different regioselectivities observed with 5. This study is extended to cyclic R-enones
and cinnamaldehyde. Similar trends hold for the former, while cinnamaldehyde always leads to
1,2-addition. The formation of intermediate complexes allows us to rationalize the cinnamaldehyde
behavior but is insufficient to explain the 1,4-addition with cyclic R-enones lying in an s-trans
conformation.
Sch em e 1
In tr od u ction
Carbanions R to nitriles are useful reagents for C-C
bond formation in organic synthesis. The study of the
regioselectivity of the reaction of these carbanions toward
R-enones was extensively studied by our group and
others.1,2 It was shown that different parameters such
as structures of the anionic species and R-enone, medium,
temperature, concentration, and added salts play an
important role in the 1,2- vs 1,4-addition. Lithiated
phenylacetonitrile (1) afforded 1,2- or 1,4-addition de-
pending on the experimental conditions.2 Such was also
the case for lithiated cyanohydrin ethers,3 cyanosilyl
ethers4 and phosphonitriles.5 On the other hand, lithi-
ated 3-pyridylacetonitrile2a and (N,N-dimethylamino)phe-
nylacetonitrile6 gave 1,4-addition essentially.
For a better understanding of the structural param-
eters of the anionic species that may control the 1,2- vs
1,4-regioselectivity, we have performed IR, NIR FT-
Raman, and 13C NMR spectroscopic studies of lithiated
phenylacetonitrile (1) in THF, THF-hexane, and THF-
(1) (a) Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Eds; Pergamon Press: London, 1991; Vol. 4. (b) Arseniyadis, S.; Kyler,
K. S.; Watt, D. S. Org. React. 1984, 31, 1-364.
toluene. We have shown that only two species are in
equilibrium in these media: a monomeric lithium-bridged
ion pair 2 and a dimeric lithium ion pair 47 (Scheme 1).
In THF, monomeric species predominates at C ) 0.25
M while dimeric species increases as the amount of
hexane or toluene in THF solution increases. Our
preliminary results have shown2a a change of the 1,2/1,4
ratio, from 95/5 in THF down to 8/92 in THF-hexane
(50/50 v/v) in the case of the reaction of 1 with benzylide-
neacetone 5 at C ) 0.25 M at -80 to -90 °C.
(2) (a) Croizat, D.; Seyden-Penne, J .; Strzalko, T.; Wartski, L.;
Corset, J .; Froment, F. J . Org. Chem. 1992, 57, 6435. (b) Strzalko, T.;
Seyden-Penne, J .; Wartski, L.; Froment, F.; Corset, J . Tetrahedron Lett.
1994, 35, 3935. (c) Sauveˆtre, R.; Roux-Schmitt, M. C.; Seyden-Penne,
J . Tetrahedron 1978, 34, 2135. (d) Roux, M. C.; Wartski, L.; Seyden-
Penne, J . Tetrahedron 1981, 37, 1927. (e) Hatzigrigoriou, E.; Wartski,
L.; Seyden-Penne, J .; Toromanoff, E. Tetrahedron 1985, 41, 5045.
(3) (a) Stork, G.; Ozorio, A. A.; Leong, A. Y. W. Tetrahedron 1978,
5175. (b) Roux, M. C. Seuron, N.; Seyden-Penne, J . Synthesis 1983,
494.
(4) Hunig, S.; Wehner, G. Chem. Ber. 1980, 113, 302.
(5) Deschamps, B. Tetrahedron 1978, 34, 2009.
(6) (a) Zervos, M.; Wartski, L.; Seyden-Penne, J . Tetrahedron 1986,
42, 4963. (b) Enders, D.; Kirchoff, J .; Mannes, D.; Raabe, G. Synthesis
1995, 659. (c) Roux, M. C.; Wartski, L.; Nierlich, M.; Lance, M.
Tetrahedron 1994, 50, 8445.
(7) Strzalko, T.; Seyden-Penne, J .; Wartski, L.; Corset, J .; Castella-
Ventura, M.; Froment, F. J . Org. Chem. 1998, 63, 3287-3294.
S0022-3263(97)01517-X CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/15/1998

3296 J . Org. Chem., Vol. 63, No. 10, 1998
Strzalko et al.
Ta ble 1. Stu d y of th e Rea ction of Lith ia ted P h en yla ceton itr ile 1a w ith Ben zylid en ea ceton e (5) a t -80 to -90 °C.
In flu en ce of Solven t, Con cen tr a tion C, a n d Rea ction Tim e on th e 1,2- vs 1,4-Regioselectivity
yieldb (%)
entry
solvent v/v
concentration C of 1c
reaction time (min)
SM
1,2
1,4
1,2/1,4 ratio
1
2
3
4
5
6
7
8
9
THF
THF
THF
THF
THF
THF
THF
0.06
0.12
0.12
0.25
0.25
0.5
5
5
30
5
30
5
30
5
9
6
6
6
5
18
18
38
41
46
32
89
89
88
87
89
74
72
46
32
28
22
2
5
6
7
6
97/3
95/5
94/6
93/7
93/7
91/9
88/12
75/25
54/46
51/49
32/68
8
0.5
10
16
27
26
46
THF-toluene 70/30
THF-toluene 50/50
THF-toluene 50/50
THF-toluene 30/70
0.25
0.25
0.25
0.25
5
30
5
10
11
a
b
The base used was 1.2 equiv of 1 M LHMDS in THF. Yield (%) determined by 1H NMR integration of the methyl signals. SM
:
unreacted 5. c The concentration is given in mol L-1
.
Sch em e 2
used. The allylic alcohol 6 (1,2-adduct) and γ-cyano
ketone 7 (1,4-adduct) were previously described.2c,d
The results concerning the influence of solvent, con-
centration, and reaction time on the 1,2- vs 1,4-regiose-
lectivity of the reaction of 1 with 5 at -80 to -90 °C are
presented in Table 1. In THF, after 5 min of reaction, a
87-89% yield of 1,2-adduct is observed for concentration
values of 0.06, 0.12, and 0.25 M, which falls to 74% at C
) 0.5 M (Table 1, entries 1, 2, 4, and 6). Conversely, a
small increase of 1,4-addition is registered, reaching a
8% yield at C ) 0.5 M.
By adding toluene to THF solutions: 30, 50, and 70%
(Table 1, entries 8, 9, and 11) the proportion of 1,4-adduct
varies from 16 up to 46% after 5 min of reaction. Thus,
in THF-toluene mixtures, 1,4-addition depends on the
percentage of added toluene to THF solutions. The same
results are obtained after 30 min of reaction either in
THF (Table 1, entries 3, 5, and 7 compared to 2, 4, and
6, respectively) or in THF-toluene medium 50/50 v/v
(Table 1, entries 9 and 10). These observations evidence
the stability of 1,2- and 1,4-adducts at -80 to - 90 °C in
all these media, during the above-mentioned reaction
times.
In flu en ce of th e Tem p er a tu r e. Chabanel has re-
ported8 that the dimerization equilibrium of LiSCN
monomeric ion pairs is entropy driven and slightly
temperature dependent. To get an insight into the
equilibrium between monomeric and dimeric species of
lithiated phenylacetonitrile (1), when the temperature is
lowered from 20 to -80 or -90 °C, we have compared
the 13C chemical shifts of C1′ and C6′ atoms of 1 at 20 °C
(C ) 0.25 M) in THF-HMPA 35/65 v/v, THF, and THF-
toluene 30/70 v/v with those at - 90 °C in THF solution
(Table 2). From the integrated molar absorption coef-
ficients previously measured7 by IR, we have determined
the monomer and dimer concentrations in THF and
THF-toluene solutions at 20 °C. The 13C chemical shifts
of the monomer δm and dimer δd are thus calculated at
20 °C (Table 2) from a molar fraction equal to 0.89 for
the monomeric species in THF and to 0.81 for the dimeric
species in THF-toluene 30/70 v/v. These values con-
firmed the noticeable high-frequency shift of C1′ and C6′
atoms when going from the free anion (THF-HMPA) to
the monomer (THF) and to the dimer (THF-toluene).
The experimental 13C chemical shifts observed at - 90
°C in THF are at a lower frequency than the calculated
Herein, we examine the 1,2- vs 1,4-regioselectivity of
the reaction of 1 with 5 in THF, in a range of concentra-
tions C ) 0.06-0.5 M at low temperature. We also
extend this study to different THF-toluene media at C
) 0.25 M. To check the formation of 1,2- and 1,4-adducts
under kinetic control, this reaction is carried out at
different times. The correlation between the concentra-
tions of 1,2- and 1,4-adducts at -80 to -90 °C in all these
media and those of the species present in solution and
determined by IR at room temperature is reported. The
temperature difference between the reactivity experi-
ments and IR is discussed. The influence of the aggrega-
tion state of 1 on the 1,2- vs 1,4-regioselectivity is
generalized to various R,â-unsaturated carbonyl com-
pounds. The diastereoselectivity of the reaction of 1 with
all these compounds is described. The results are
interpreted in terms of “intermediate complexes” involv-
ing either a monomeric or a dimeric species.
(1) Regioselectivity Stu d y. (1-1) Rea ction of 1
w ith Ben zylid en ea ceton e (5). 1,2- a n d 1,4-Ad d u ct
F or m a tion (Sch em e 2). LHMDS (1 M, 1.2 equiv) in
THF solution was added to 1 equiv of phenylacetonitrile
(1) in THF under argon at 20 °C, the concentrations being
C ) 0.06, 0.12, 0.25, and 0.5 M. After being stirred for
30 min, the solution was cooled at -80 to -90 °C and 1
equiv of benzylideneacetone (5) was added. The reaction
medium was stirred during 5 or 30 min at -80 to -90
°C and then quenched by slow addition of 2 M HCl
aqueous solution to limit a too fast temperature increase.
After the usual workup, the crude product was analyzed
by 1H NMR. In some cases an internal standard was
(8) (a) Chabanel, M.; Paoli, D. J . Chim. Phys. 1980, 77, 913. (b)
Chabanel, M. Pure Appl. Chem. 1990, 62, 35.

Regioselectivity of Lithiated Phenylacetonitrile
J . Org. Chem., Vol. 63, No. 10, 1998 3297
Ta ble 2. Exp er im en ta l 13C NMR Ch em ica l Sh ifts of C1′
a n d C6′ of 1 (C ) 0.25 M) a t 20 °C for th e F r ee An ion , th e
Mon om er , th e Dim er , a n d a t -90 °C for th e Mon om er .
Com p a r ison w ith th e Ca lcu la ted Sh ifts of th e Mon om er
a n d Dim er a t 20 °C
solvent v/v
δa
δC1′
δC6′
THF-toluene 30/70
THF
THF
THF-HMPA 35/65
THF
expb
150.3
144.3
139.6
134.3
143.0
152.1
114.5
112.0
110.4
107.5
111.5
115.2
expb
expc
expb
d
calcd δm
calcd δd
d
THF-toluene 30/70
a
b
δ are given in ppm downfield from TMS. δ at 20 °C. c δ at
d
-90 °C. Calculated from a molar fraction equal to 0.89 for the
monomeric species in THF and to 0.81 for the dimeric species in
THF-toluene 30/70 v/v7at 20 °C.
ones δm for the monomeric species at 20 °C in THF: 3.4
ppm for C1′ and 1.1 ppm for C6′. These values are too
large to be assigned to a simple temperature effect that
is usually of the order of 10-3 ppm per degree.9 Similar
variations were observed when going from the monomer
to the free anion, 8.7 and 4.0 ppm, respectively. The
dependence of the 13C data with temperature indicates
a strengthening of the cation solvation at low tempera-
ture, reducing its polarization effect on the anion.
We may thus conclude that the equilibrium between
monomeric and dimeric species (which is entropy driven
with probably a small positive enthalpy value) is shifted
in THF at - 90 °C toward the monomeric species, the
molar fraction of the monomeric species varying from
0.89 to 1. This small influence of the temperature on
the equilibrium justifies the further correlation between
the concentration of the species at 20 °C measured by
IR with those of the 1,2- and 1,4-adducts formed at -80
to -90 °C in the same media.
F igu r e 1. Diagram for the determination of the integrated
molar absorption coefficients of the monomeric species 2 and
of the dimeric species 4 in THF solution.7 Concentrations C
in mol L-1 are for the following points: 1, 0.5; 2, 0.4; 3, 0.25;
4, 0.24; 5, 0.20; 6, 0.12; 7, 0.10; 8, 0.06; 9, 0.06.
IR Con cen tr a tion Mea su r em en ts. We have deter-
mined the concentrations of the species 2 (Cm) and 4 (Cd)
in THF at C concentrations in the range 0.06-0.5 M, as
previously described,7 following the method proposed by
Chabanel and Paoli.8a As shown for LiSCN,8a the IR
bandwidth may increase with concentration. We have
thus performed this study with a more elaborate treat-
ment of the spectra of 1 involving the sum of four
components at 2090 and 2083 cm-1 for 2, and 2072 and
2058 cm-1 for 4. The integrated intensity of each band
was measured for concentrations: C ) 0.5, 0.4, 0.25, 0.24,
0.20, 0.12, 0.10 and 0.06 M, the bandwidth increasing
slightly with concentration. The ratio of the integrated
intensities of νas (2058 cm-1) over νs (2072 cm-1) bands
of the dimer was found equal to 5.2 ( 1 in the concentra-
tion range 0.5-0.12 M; this ratio is in agreement with a
small distortion of the quasi centrosymmetric dimer,
which leads to a small activity of the νs mode in IR. On
the other hand, the ratio of the integrated intensities of
the bands at 2090 and 2083 cm-1 of the monomer was
equal to 1.82 ( 0.2 in the same concentration range,
indicating a strong intensity exchange through a Fermi
resonance with a combination or overtone mode. We
have thus considered Am as the sum of the integrated
intensities of the bands at 2090 and 2083 cm-1 and Ad
as the integrated intensity of the band at 2058 cm-1. The
variations of Am/lC versus Ad/lC are shown in Figure 1.
In the concentration range 0.12-0.5 M (Figure 1, points
1-6) a quasilinear variation was observed as shown
previously for THF-toluene and THF-hexane media (ref
7, Figure 4). This is not the case at lower concentrations
(Figure 1, points 7-9). The ratio of the integrated
intensities of the dimer νas/νs falls down to 3.5 and 2 (
0.5 at C ) 0.1 M and 0.06 M, respectively. These results
suggest that, at concentrations smaller than 0.12 M,
another species appears with a ν(CtN) mode around
2072 cm-1. This species is probably a lithiated linear
monomeric ion pair, whose ν(CtN) wavenumber is as
expected close to that of the dimeric species.7
The concentrations Cm of the bridged monomer 2 and
Cd of the dimer 4 were calculated from ꢀm and ꢀd (part I,
eq 6) as previously described.7 ꢀm and ꢀd were determined
from the intersections of the straight line with the axis
(Figure 1). The Cm and Cd values are presented in Table
3.
We have calculated the apparent equilibrium constant8a
Kapp ) Cd/C2 at concentrations varying from 0.5 to 0.06
m
2
M (Table 3). The equilibrium constant K ) Kappγd/γm
involves the activity coefficients γm and γd of the monomer
and dimer, respectively. Taking into account the ac-
curacy of the measurements and neglecting the possible
variation of these coefficients, we may consider K as
constant in the concentration range 0.5-0.12 M. This
is in favor of an equilibrium between only bridged
monomers and dimers. The fact that the sum Cm + 2Cd
(Table 3) is equal to the total concentration C, in the
above concentration range, is also in agreement with this
single equilibrium.
(9) Morin, F. G.; Solum, M. S.; Withers, J . D.; Grant, D. M. J . Magn.
Reson. 1982, 48, 138.

3298 J . Org. Chem., Vol. 63, No. 10, 1998
Strzalko et al.
Ta ble 3. Deter m in a tion of th e Con cen tr a tion s Cm of 2
a n d Cd of 4 fr om th e IR In tegr a ted In ten sities Am a n d Ad
of th e ν(CtN) Ba n d s in THF a t Differ en t Con cen tr a tion s
a n d Com p a r ison w ith th e Con cen tr a tion s C1,2 a n d C1,4 of
th e Ad d u cts F or m ed w ith 5
point
no.
Ca
Cm
Cd
Cm + 2Cd Kapp C1,2
C1,4 C1,2 + C1,4
b
b
c
d
d
0.50
0.40
0.25
0.24
0.20
0.12
0.10
0.06
0.06
1
2
3
4
5
6
7
8
9
0.363 0.070
0.305 0.048
0.218 0.024
0.201 0.025
0.161 0.016
0.102 0.008
0.080 0.005
0.047 0.002
0.042 0.002
0.503
0.401
0.266
0.251
0.193
0.118
0.090
0.051
0.046
0.53 0.365 0.045
0.51
0.50 0.220 0.016
0.62
0.410
0.236
0.62
0.77 0.106 0.007
0.78
0.90 0.053 0.001
1.13
0.113
0.054
a
b
Concentrations are given in mol L-1
.
Cm ) Am/lꢀm and Cd )
Ad/lꢀd, where ꢀm and ꢀd are deduced from eq 6 as in ref 7, from the
c
intersections of the straight line with the axis in Figure 1. Kapp
2
d
) Cd/Cm is given in mol-1 L. C1,2 and C1,4 are deduced from the
yields reported in Table 1, after 5 min of reaction time.
At concentrations lower than 0.12 M, the increase of
Kapp is probably due to the low accuracy of the measure-
ments and to the variation of activity coefficients. The
comparison of the total concentration C with the calcu-
lated sum Cm + 2Cd confirms the presence of another
species.
F igu r e 2. Correlation between the concentrations C1,2 of the
1,2-adduct and Cm of the monomeric species 2 (points 1-4,
Table 4) and correlation between the concentrations C1,4 of the
1,4-adduct and Cd of the dimeric species 4 (points 1′-4′, Table
4) in THF-toluene media (C ) 0.25 mol L-1). C1,2 and C1,4 are
determined from Table 1. Cm and Cd are measured from Am,
Ad and ꢀm, ꢀd (Table 4).
In THF-toluene and THF-hexane solvent mixtures
at C ) 0.25 M, the concentrations Cm and Cd were
calculated from the integrated intensities of the ν(CtN)
bands of the monomer 2 (2090 cm-1) and dimer 47 (νas
)
2058 cm-1) and presented in Table 4. There is an
excellent correlation between the calculated Cm + 2Cd
value and that of the total concentration C, confirming
the presence of an equilibrium between only monomers
and dimers, as shown previously.7
Cor r ela tion betw een Con cen tr a tion s Cm a n d Cd
a n d 1,2- a n d 1,4-Ad d u cts Resp ectively. In THF at
different concentrations C, the concentrations of the 1,2-
adduct (C1,2) and of the 1,4-adduct (C1,4) obtained by
reacting 1 with 5 at -80 to -90 °C during 5 min are
presented in Table 3. They were calculated from the
corresponding yields reported in Table 1. Tables 1 and
3 indicate a good correlation between the concentrations
of the monomeric species Cm and C1,2. From Table 1, it
appears also that the yield of the highly predominant 1,2-
adduct remains constant after 5 and 30 min of reaction.
This result is in line with a kinetic control of the 1,2-
process.
In THF-toluene and THF-hexane media at C ) 0.25
M, the concentrations C1,2 and C1,4 of the 1,2- and 1,4-
adducts are reported in Table 4. They were calculated
from the corresponding yields presented in Table 1 for
THF-toluene media and ref 2b for THF-hexane media.
The variations of C1,2 and C1,4 as a function of Cm and
Cd, respectively, are presented in Figures 2 and 3. Figure
2 shows a linear correlation between Cm and Cd and C1,2
and C1,4, respectively, in THF-toluene media with a slope
of 1. This implies that, at low temperature, the reaction
of the monomeric species 2 and of the dimeric species 4
with 5, respectively, is much faster than their intercon-
version. Consequently, these processes take place under
kinetic control. This one was also confirmed by the
stability of the 1,2- and 1,4-adducts at -80 °C after 30
min of reaction time in THF-toluene 50/50 v/v (Table 1,
entry 10).
F igu r e 3. Correlation between the concentrations C1,2 of the
1,2-adduct and Cm of the monomeric species 2 (points 1-5,
Table 4) and correlation between the concentrations C1,4 of the
1,4-adduct and Cd of the dimeric species 4 (points 1′-5′, Table
4) in THF-hexane media (C ) 0.25 mol L-1). C1,2 and C1,4 are
taken from ref 2b. Cm, Cd are measured from Am, Ad and ꢀm, ꢀd
(Table 4).
well only at low concentrations in hexane (18%). At
higher concentrations of hexane (up to 50%), C1,4 is higher
than expected from Cd whereas C1,2 is lower than
expected from Cm. This result may be explained by the
insolubility of the monomer 2 when the temperature
decreases.
In THF-hexane media (Figure 3), the correlation
between Cm and Cd and C1,2 and C1,4, respectively, fits

Regioselectivity of Lithiated Phenylacetonitrile
J . Org. Chem., Vol. 63, No. 10, 1998 3299
Ta ble 4. Deter m in a tion of th e Con cen tr a tion sa Cm of 2 a n d Cd of 4 fr om th e IR-In tegr a ted In ten sities Am a n d Ad of th e
ν(CtN) Ba n d s in THF -Tolu en e a n d THF -Hexa n e Med ia a n d Com p a r ison w ith th e Con cen tr a tion s C1,2 a n d C1,4 of th e
Ad d u cts F or m ed fr om 5 a t C ) 0.25 M
point
solvent v/v
no.
Cm
C1,2
point no.
Cd
C1,4
Cm + 2Cd
C1,2 + C1,4
THF-toluene
30/70
1
2
0.027
0.088
0.088
0.089
0.089
0.138
0.145
0.201
0.201
0.055
0.080
0.070
0.080
0.070
0.115
0.115
0.197
0.217
1′
2′
0.117
0.098
0.098
0.071
0.071
0.052
0.051
0.025
0.025
0.115
0.067
0.065
0.067
0.065
0.040
0.040
0.020
0.017
0.261
0.284
0.284
0.231
0.231
0.242
0.247
0.251
0.251
0.170
0.147
0.135
0.147
0.135
0.155
0.155
0.217
0.234
50/50
70/30
100
3
4
3′
4′
THF-hexane
50/50
1
2
3
4
5
0.082
0.108
0.151
0.169
0.200
0.011
0.027
0.048
0.146
0.218
1′
2′
3′
4′
5'
0.075
0.063
0.058
0.040
0.027
0.120
0.081
0.054
0.049
0.012
0.232
0.234
0.267
0.249
0.254
0.131
0.108
0.102
0.195
0.230
60/40
70/30
82/18
100
a
Cm, Cd, C1,2, and C1,4 are given in mol L-1
.
Ta ble 5. Rea ctivity of 1 tow a r d r,â-Un sa tu r a ted Ca r bon yl Com p ou n d sa
The difference between the sum C1,2 + C1,4 and C,
reported in Table 4, is due to unreacted benzylideneac-
etone (5) and seems to indicate that the dimer reacts with
only one molecule of 5.
Several points concerning the regioselectivity of these
reactions can be outlined:
In THF medium, the 1,2/1,4 ratio falls from 95/5 with
5 down to 53/47 and 71/29 with cyclic R-enones; never-
theless, the 1,2-adduct remains the major product.
(1-2) Gen er a liza tion of th e Rea ction of 1 w ith
Oth er r,â-Un sa tu r a ted Ca r bon yl Com p ou n d s. The
reaction of 1 with 2-cyclohexen-1-one, 3-methyl-2-cyclo-
hexen-1-one, and cinnamaldehyde was carried out in
THF, THF-toluene 30/70 v/v, and THF-hexane 50/50
v/v at C ) 0.25 M, the temperature being kept at -80 to
-90 °C during 5 min, as described above. After the
reaction medium was quenched by 2 M HCl aqueous
solution, the 1,2- and 1,4-adducts previously reported2,10
were characterized by 1H NMR of the crude products. The
results are shown in Table 5.
In THF-toluene and in THF-hexane solvent mix-
tures, the 1,4-addition predominates with all R-enones,
as we already noticed for 5.
Cinnamaldehyde leads to the 1,2-adduct whatever the
medium is, THF, THF-toluene, or THF-hexane.
The yields of the reactions performed in media that
favor association are generally lower than those obtained
in THF medium for R-enones as well as for cinnamalde-
hyde. Although the kinetic control is not ascertained in
the case of these R-enones, we also envisaged that
monomeric species are responsible for the 1,2-adducts,
whereas dimeric species give the 1,4-adducts.
(10) El-Bouz, M.; Wartski, L.; Seyden-Penne, J . J . Organomet. Chem.
1979, 177, 17.

3300 J . Org. Chem., Vol. 63, No. 10, 1998
Strzalko et al.
F igu r e 4. Models constructed for the intermediate complexes between benzylideneacetone (5) and the lithium-bridged monomer
2 using the molecular geometry of 5 and the calculated structure of 2. The following fixed parameters for the intermolecular
distances and angles are used: (a) the Li+ cation is coordinated to the oxygen lone pair of 5 in the s-trans conformation with the
parameters O1Li ) 2.08 Å, LiO1C2 ) 120°, O1LiC2′ ) 110°, which are kept constant in all schemes; (b) and (c) 5 in the s-cis or
s-trans conformation is rotated around the C2O1 axis until its plane is almost parallel to that of the phenylacetonitrile anion. The
distances and angles are as follows: (b) C2C2′ ∼3.6 Å; C2′C2O1 ∼73°; C2′C4′ ∼4.5 Å; (c) C2′C2 ∼3.6 Å; C2′C2O1 ∼73°; C2′C4 ∼5.4 Å.
(2) Dia ster eoselectivity Stu d y. A poor diastereo-
selectivity was observed with R-enones for both 1,2- and
1,4-adducts in the media studied at C ) 0.25 M (Table
5). With cinnamaldehyde, a higher diastereoselectivity,
about 85/15, was obtained in THF and THF-toluene
solutions. For both benzylideneacetone and cinnamal-
dehyde, the diastereoselectivity was not modified by
diluting the THF solution from C ) 0.25 M to C ) 0.06
M. A significant improvement of the diastereoselectivity
was reported when the reaction of PhCHCNLi was
performed with aldehydes bearing a bulky secondary or
tertiary substituent11,12 at low concentration (C ) 0.025
M). In the cases we have studied, there is no clear
relationship between the degree of aggregation of 1 and
the diastereoselectivity observed at C ) 0.25 M and C )
0.06 M.
s-trans conformation of 5 (Figures 4b,c and 5b,c). In the
case of the 1,2-addition, both the C2′C2 distance (∼3.6 Å)
and the C2′C2O1 angle (∼73°) allow the development of a
favorable C2′π* interaction, whatever the s-cis or s-trans
conformation of 5 (Figure 4b,c). These models are quite
similar to the transition structures calculated by ab initio
methods for the reaction of monomeric methyllithium
with formaldehyde.13 On the other hand, only the
approach using 5 in an s-cis conformation (Figure 5b) is
in agreement with a C4 attack, leading to 1,4-addition,
the shortest distance being the C2′C4 one (∼3.9 Å). This
is no longer the case when 5 is in an s-trans conformation,
the C2′C4 distance (∼5.7 Å) being not the shortest one.
In the same way, the simple models proposed for 5 are
not valid for 2-cyclohexen-1-one and 3-methyl-2-cyclo-
hexen-1-one lying in an s-trans conformation. Neverthe-
less, the exclusive 1,2-addition observed with cinnama-
ldehyde in THF-toluene and THF-hexane media may
also imply dimeric species. If its conformation is as-
sumed to be s-trans, the model shown in Figure 5c may
account for the 1,2-regioselectivity (C2′′C2 ∼4.5 Å). The
low 1,2-adduct yield fits well with this hypothesis. The
intermediate complexes presented in Figure 5b,c and
involved in these processes may lead to open dimers via
the breakup of one LiN bond. Such open dimers are
described in ab initio calculations of the reaction of
solvated dimeric methyllithium with formaldehyde.13,15
(3) In ter m ed ia te Com p lex Mod els. Assuming an
early transition state on the reaction pathway,13
a
qualitative approach of the reactants is proposed using
geometric models.
Intermediate complexes between either the bridged
monomeric 2 or the dimeric ion pair 4 are involved,
allowing the oxygen lone pair and the lithium p orbital
interactions in the carbonyl plane of the benzylideneac-
etone (5) in an s-cis or s-trans conformation. The O1Li
distance was set equal to 2.08 Å (sum of the ionic radius
of Li and of the van der Waals radius of O1).14 The
formation of one of the diastereomers is shown in Figures
4a and 5a, 5 being represented only in an s-trans or in
an s-cis conformation.
Con clu sion
In THF, and in media that favor association, such as
THF-toluene solvent mixtures, the reaction of ben-
zylideneacetone (5) with lithiated phenylacetonitrile (1)
proceeds under kinetic control: the concentrations of 1,2-
and 1,4-adducts are directly related to the concentrations
of monomeric 2 and dimeric 4 species, respectively. In
THF, the monomeric bridged ion pair 2 leads to predomi-
nately 1,2-addition with R,â-unsaturated carbonyl com-
pounds. High 1,4-regioselectivity is evidenced with
A simple rotation around the CO1 axis brings the
planes of 5 and of the carbanion parallel and leads for
each complexe to two approaches related to the s-cis or
(11) Carlier, P. R.; Lo, K. M. J . Org. Chem. 1994, 59, 4053.
(12) Carlier, P. R.; Lo, K. M.; Williams, I. D. J . Org. Chem. 1995,
60, 7511.
(13) Kaufmann, E.; Schleyer, P. v. R.; Houk, K. N.; Wu, Y. D. J .
Am. Chem. Soc. 1985, 107, 5560.
(14) Baron, M. H.; J aeschke, H.; Moravie, R. M.; De Loze, C.; Corset,
J . Metal-ligand interactions in organic chemistry and biochemistry;
Pullmann, B., Goldblum, N., Eds.; Reidel D. Publishing Co: Dordrecht,
Holland, 1977, Part 1, p 171.
(15) Nakamura, M.; Nakamura, E.; Koga, N.; Morokuma, K. J . Am.
Chem. Soc. 1993, 115, 11016.

Regioselectivity of Lithiated Phenylacetonitrile
J . Org. Chem., Vol. 63, No. 10, 1998 3301
3-methyl-2-cyclohexen-1-one, and cinnamaldehyde are J anssen
products and were distilled prior to use. LHMDS (1 M in THF)
and n-Buli (1.6 M in hexane) are Aldrich commercial solutions.
IR spectra were scanned using a Perkin-Elmer 983 spec-
trometer at 3 cm-1 resolution. The CaF2 cell thickness was
0.0037, 0.0052, or 0.0096 cm depending on the concentration
of the solutions. The preparation of the anion solutions and
the filling of the cells were performed at 20 °C under argon in
a glovebag.2a The different concentrations of the solutions (C
) 0.5, 0.4, 0.25, 0.24, 0.20, 0.12, 0.10 M) were obtained directly
and also by dilution of the parent solution.
1H NMR spectra were recorded on a Bruker AM 250
spectrometer, the solvent being CDCl3 or C6D6.
13C NMR spectra were recorded on a Bruker AM 250 or 400
spectrometer as in ref 2.
A typical procedure for addition of lithiated phenylacetoni-
trile (1) to benzylideneacetone (5) (Table 1) follows. In a 50
mL oven-dried three-necked round-bottomed flask fitted with
a rubber septum, a thermometer, and a mechanical stirrer was
placed under argon phenylacetonitrile (3 mmol for C ) 0.5 and
0.25 M; 2 mmol for C ) 0.12 M; 1 mmol for C ) 0.06 M) in the
required amount of solvent (THF or THF-toluene) so that the
final concentration of 1 in the solution was 0.5, 0.25, 0.12, or
0.06 M after addition of base and of 5. The anion was formed
by adding dropwise at room temperature via a well-dried
syringe purged with argon 1.2 equiv of 1M LHMDS in THF
under stirring. After 30 min, the reaction mixture was cooled
between -80 and -90 °C. A stoichiometric amount of ben-
zylideneacetone (5) dissolved in 0.5 mL of solvent was added
dropwise via a dried syringe to the stirred solution between
-85 and -90 °C during 1 min. The reaction medium was then
stirred during the times indicated in Table 1 and then
quenched with an aliquot amount of 2 M HCl aqueous solution
(5 mL for 3 mmol of 5, for instance) added slowly dropwise
via a syringe in order to limit the temperature increase of the
reaction medium.
It is very important to quench the reaction medium very
slowly, especially at C ) 0.5 M in THF, otherwise less 1,2-
adduct and more starting materials were found. This quench-
ing step is crucial for the reproduction of the results. The
choice of the hydrolyzing agent is also important as this
reaction takes place in heterogeneous conditions. Poorer yields
were obtained with 1 M HCl (10 mL for 3 mmol of 5) or
saturated NH4Cl (5 mL for 3 mmol of 5) aqueous solutions.
The cooling bath was removed after complete addition of
HCl, and the reaction mixture was diluted at room tempera-
ture with 30 mL of ether. The combined organic layers were
washed three times with 30 mL of brine and then dried over
anhydrous MgSO4. In some cases, benzyl benzoate was added
as internal standard in equimolecular amounts to determine
the yield of 1,2- and 1,4-adducts 6 and 7, respectively. The
solvents were removed under reduced pressure to afford an
F igu r e 5. Models constructed for the intermediate complexes
between benzylideneacetone (5) and the dimer 4 using the
molecular geometry of 5 and the X-ray data7 of the dimer. The
following fixed parameters, for the intermolecular distances
and angles are used: (a) the Li+ cation is coordinated to the
oxygen lone pair of 5 in the s-cis conformation with the
parameters O1Li ) 2.08 Å, LiO1C2 ) 120°, O1LiC2 ) 110°,
which are kept constant in all schemes; (b) and (c) 5 in the
s-cis or s-trans conformation is rotated around the C2O1 axis,
until its plane is almost parallel to that of the phenylaceto-
nitrile anion. The distances and angles are the following: (b):
C2′C4 ∼3.9 Å; C2′C4C3 ∼124°; C2′C2 ∼5.2 Å; C2′C2O1 ∼65°; C2"C2
∼ 4.5Å; C2"C2O1 ∼80°; C2"C4 ∼6.5 Å; C2′′C4C3 ∼47°; (c): C2′′C2
∼4.5 Å; C2′′C2O1 ∼80°; C2′′C4 ∼6.2 Å; C2′′C4C3 ∼62°; C2′C2 ∼5.2
Å; C2′C2O1 ∼65°; C2′C4 ∼5.7 Å; C2′C4C3 ∼41°.
1
oil that was examined by H NMR in CDCl3. The yields were
determined by integration of the signals of methyl protons of
5-6 and 7 (altogether 100%) or by integration of these same
signals relative to the methylene protons of the benzyl ben-
zoate standard. The yields reported in Table 1 are close to
those determined with the internal standard. About 10% of
products were lost during extraction. 1,2- and 1,4-adducts were
previously described.2c
R-enones in media that favor association, while only 1,2-
regioselectivity is observed with cinnamaldehyde what-
ever the media is. The formation of intermediate com-
plexes is proposed and may satisfactorily account for the
different regioselectivities observed either with the mono-
meric bridged ion pair 2 or with the dimeric aggregate 4
in the case of 5. The intermediate complex model
between 4 and cinnamaldehyde in an s-trans conforma-
tion also allows us to explain the 1,2-regioselectivity
observed. However, the 1,4-adducts obtained with 2-cy-
clohexen-1-ones are more difficult to interpret.
The generalization of the reaction of 1 with other R,â-
unsaturated carbonyl compounds, shown in Table 5, was
achieved as above. The reactions were carried out at C ) 0.25
M during 5 min between -80 and -90 °C to provide the
2c,d,10
corresponding adducts that were already described.
The 1H NMR spectra of the products obtained from 2-cy-
clohexen-1-ones were run in C6D6, allowing a better splitting
of the R to CN protons on which integration was performed.
With cinnamaldehyde, the analysis was realized in CDCl3 as
above.
Ack n ow led gm en t. We thank J .M. Dedieu for run-
ning 13C NMR spectra and J . P. Brun for construction
of models of Figures 4 and 5.
Exp er im en ta l Section
Tetrahydrofuran was distilled from sodium benzophenone
and kept under argon. Toluene was distilled over CaH2 and
hexane over P2O5. Phenylacetonitrile, 2-cyclohexen-1-one,
J O9715175